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  • depicts the synthesis of series with a four

    2022-05-16

    depicts the synthesis of series with a four-step sequence. First, the commercially available 4-hydroxybenzaldehyde () was condensed with 2-bromoethanol through Mitsunobu reaction to give the key intermediate (). Next, conventional nucleophilic substitution reaction with the privileged structures (–) using a variety of deprotonating bases, yielded their congruent aldehydes (). The R groups implicated within the scaffolds (–) were used as a handle to introduce structural diversity. Finally, the obtained aldehydes were converted to their corresponding target molecules (–) in an analogous fashion to that previously described in . It is worth noting that the hydrophobic scaffolds (–) were either commercially available or synthesized in-house. The benzimidazole ring () or its 2-methanol derivative () were constructed using Phillips procedure through an acid-catalyzed condensation of phenylenediamine with formic or glycolic acid, respectively., All synthesized target compounds were tested for their ability to activate PPAR-γ using luciferase-based genetic reporter assay. In this cell-based transcription assay, proprietary bioreporter cells were transfected with two genetic elements; the luciferase reporter gene plasmid and GAL4-PPAR-γ expression plasmid. These cells express hybrid receptors, GAL4-PPAR-γ chimeric protein, which can bind to the GAL4 Wiskostatin located upstream of the firefly luciferase reporter gene (). Activities are reported as fold-induction as well as EC. Regarding fold-induction, results obtained by test compounds were compared to negative control sample of the vehicle DMSO. Additionally, the fold-induction was also calculated as a percentage of that of rosiglitazone as a measure of compounds’ intrinsic activity (). Values ≥fivefold-induction, relative to DMSO, were considered statistically significant and may warrant further consideration. In series , modest activities were afforded with an exception of (5.2-fold activation). The reason for such modest potency might be attributed to the bulky branched hydrophobic tail. In both series, and , four atoms separate the large biaryl tail from the central core. This might push the terminal aromatic group too far downwards into the receptor hydrophobic pocket. On the other hand, the presence of the methoxy group in might favour polar interactions with the receptor pocket. Interestingly, the same observation was also noticed with the methoxy derivative of our reported series (phenoxybenzyl-chemotype). It is worth noting that, introducing a different electron withdrawing H-bonding group (CF in ) completely abolished the activity. To our delight, seven compounds showed future prospection with members of series showed more significant PPAR-γ transactivation. The activities afforded by this series were greater than or equal fivefold-induction with three compounds (,,) exceeding the 30-fold-induction border. Interestingly, and showed the full agonist profile with maximum fold-activation up to 130%, relative to that of rosiglitazone. As reported, a hydrophobic tail bearing H-bond acceptors may enhance the PPAR-γ transactivation. This could explain the improved activity of this series, together with suitable size and shape of the indole privileged scaffold. Regarding our synthesized compound , its design rational was set to further explore the benzimidazole motif as being an advantageous indole-bioisostere capable of providing extra-hydrogen bonding at the tail pocket of both receptors. Moreover, the possibility of different linking position at the benzimidazole ring, in comparison to the , would introduce more spacial-occupation for the overall structure allowing more favored pocket accommodation. However, the low activities depicted by suggested a non-tolerable substitution at C-2, possibly due to steric clashes, the thing being assumed since also depicted low activity range. A calcium flux FLIPR assay was implemented to assess the FFAR1 transactivation capability of our synthesized compounds (). This functional cell-based assay utilized CHO-K1/FFA1/Gα15 stable cell line (). Comparing both series, the fused ring scaffold (series ) showed better activities in the low micromolar range. This could be related to the resemblance between both the most potent FFAR1 ligands (biphenyl-based agonists) and fused ring chemotype regarding linearity.